Compliant implantable medical devices and methods of making same

ABSTRACT

Implantable medical grafts fabricated of metallic or pseudometallic films of biocompatible materials having a plurality of microperforations passing through the film in a pattern that imparts fabric-like qualities to the graft or permits the geometric deformation of the graft. The implantable graft is preferably fabricated by vacuum deposition of metallic and/or pseudometallic materials into either single or multi-layered structures with the plurality of microperforations either being formed during deposition or after deposition by selective removal of sections of the deposited film. The implantable medical grafts are suitable for use as endoluminal or surgical grafts and may be used as vascular grafts, stent-grafts, skin grafts, shunts, bone grafts, surgical patches, non-vascular conduits, valvular leaflets, filters, occlusion membranes, artificial sphincters, tendons and ligaments.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/908,933, filed Jun. 3, 2013, which will issue as U.S. Pat.No. 8,910,363 on Dec. 16, 2014; which is a continuation of U.S. patentapplication Ser. No. 12/633,716, filed Dec. 8, 2009, now U.S. Pat. No.8,458,879, issued on Jun. 11, 2013; which is a divisional of U.S. patentapplication Ser. No. 11/157,139, filed Jun. 20, 2005, now U.S. Pat. No.7,641,682, issued on Jan. 5, 2010; which is a continuation of U.S.patent application Ser. No. 10/135,626, filed Apr. 29, 2002, now U.S.Pat. No. 6,936,066, issued on Aug. 30, 2005; which corresponds to andclaims priority to U.S. Provisional Patent Application Ser. No.60/302,797, filed Jul. 3, 2001; and is a continuation-in-part of U.S.patent application Ser. No. 09/443,929, filed Nov. 19, 1999, now U.S.Pat. No. 6,379,383, issued on Apr. 30, 2002; and is acontinuation-in-part of U.S. patent application Ser. No. 09/532,164filed Mar. 20, 2000, now U.S. Pat. No. 6,537,310, issued on Mar. 25,2003, all herein incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

The present invention relates generally to implantable metallic medicaldevices. When implanted into the body, metals are generally consideredto have superior biocompatibility than that exhibited by polymers usedto fabricate commercially available polymeric grafts. It has been foundthat when prosthetic materials are implanted, integrin receptors on cellsurfaces interact with the prosthetic surface. The integrin receptorsare specific for certain ligands in vivo. If a specific protein isadsorbed on a prosthetic surface and the ligand exposed, cellularbinding to the prosthetic surface may occur by integrin-ligand docking.It has also been observed that proteins bind to metals in a morepermanent fashion than they do to polymers, thereby providing a morestable adhesive surface. The conformation of proteins coupled tosurfaces of most medical metals and alloys appears to expose greaternumbers of ligands and preferentially attract endothelial cells havingsurface integrin clusters to the metal or alloy surface relative toleukocytes. Finally, metals and metal alloys exhibit greater resistanceto degradation of metals relative to polymers, thereby providing greaterlong-term structural integrity and stable interface conditions.

Because of their relatively greater adhesive surface profiles, metalsare also susceptible to short-term platelet activity and/orthrombogenicity. These deleterious properties may be offset byadministration of pharmacologically active antithrombogenic agents inroutine use today. Surface thrombogenicity usually disappears 1-3 weeksafter initial exposure. Antithrombotic coverage is routinely providedduring this period of time for coronary stenting. In non-vascularapplications such as musculoskeletal and dental, metals have alsogreater tissue compatibility than polymers because of similar molecularconsiderations. The best article to demonstrate the fact that allpolymers are inferior to metals is van der Giessen, W J. et al. Markedinflammatory sequelae to implantation of biodegradable andnon-biodegradable polymers in porcine coronary arteries, Circulation,1996:94(7):1690-7.

Normally, endothelial cells (EC) migrate and proliferate to coverdenuded areas until confluence is achieved. Migration, quantitativelymore important than proliferation, proceeds under normal blood flowroughly at a rate of 25 μm/hr or 2.5 times the diameter of an EC, whichis nominally 10 μm. EC migrate by a rolling motion of the cell membrane,coordinated by a complex system of intracellular filaments attached toclusters of cell membrane integrin receptors, specifically focal contactpoints. The integrins within the focal contact sites are expressedaccording to complex signaling mechanisms and eventually couple tospecific amino acid sequences in substrate adhesion molecules. An EC hasroughly 16-22% of its cell surface represented by integrin clusters.Davies, P. F., Robotewskyi A., Griem M. L. Endothelial cell adhesion inreal time. J. Clin. Invest. 1993; 91:2640-2652, Davies, P. F.,Robotewski, A., Griem, M. L., Qualitative studies of endothelial celladhesion, J. Clin. Invest. 1994; 93:2031-2038. This is a dynamicprocess, which implies more than 50% remodeling in 30 minutes. The focaladhesion contacts vary in size and distribution, but 80% of them measureless than 6 μm², with the majority of them being about 1 μm², and tendto elongate in the direction of flow and concentrate at leading edges ofthe cell. Although the process of recognition and signaling to determinespecific attachment receptor response to attachment sites isincompletely understood, availability of attachment sites will favorablyinfluence attachment and migration. It is known that materials commonlyused as medical grafts, such as polymers, do not become covered with ECand therefore do not heal after they are placed in the arteries. It istherefore an object of this invention to replace polymer grafts withmetal grafts that can potentially become covered with EC and can healcompletely. Furthermore, heterogeneities of materials in contact withblood flow are preferably controlled by using vacuum depositedmaterials.

There have been numerous attempts to increase endothelialization ofimplanted medical devices such as stents, including covering the stentwith a polymeric material (U.S. Pat. No. 5,897,911), imparting adiamond-like carbon coating onto the stent (U.S. Pat. No. 5,725,573),covalently binding hydrophobic moieties to a heparin molecule (U.S. Pat.No. 5,955,588), coating a stent with a layer of blue to black zirconiumoxide or zirconium nitride (U.S. Pat. No. 5,649,951), coating a stentwith a layer of turbostratic carbon (U.S. Pat. No. 5,387,247), coatingthe tissue-contacting surface of a stent with a thin layer of a Group VBmetal (U.S. Pat. No. 5,607,463), imparting a porous coating of titaniumor of a titanium alloy, such as Ti—Nb—Zr alloy, onto the surface of astent (U.S. Pat. No. 5,690,670), coating the stent, under ultrasonicconditions, with a synthetic or biological, active or inactive agent,such as heparin, endothelium derived growth factor, vascular growthfactors, silicone, polyurethane, or polytetrafluoroethylene, U.S. Pat.No. 5,891,507), coating a stent with a silane compound with vinylfunctionality, then forming a graft polymer by polymerization with thevinyl groups of the silane compound (U.S. Pat. No. 5,782,908), graftingmonomers, oligomers or polymers onto the surface of a stent usinginfrared radiation, microwave radiation or high voltage polymerizationto impart the property of the monomer, oligomer or polymer to the stent(U.S. Pat. No. 5,932,299). However, all these approaches do not addressthe lack of endothelialization of polymer grafts. The present inventionattempts to solve these problems, as well as others.

SUMMARY OF THE INVENTION

An implantable medical device, comprising: a. a body member comprising afilm having a first surface, a second surface and a thicknessintermediate the first surface and the second surface; and b. aplurality of microperforations passing through the thickness of the bodymember and communicating between the first surface and the secondsurface, whereby said plurality of microperforations impart complianceto the body member.

A method of fabricating the graft is disclosed and comprises the stepsof: a. providing a pre-existing blank of at least one of a biocompatiblemetallic and pseudometallic material; b. removing sections of thepre-existing blank material to form a plurality of microperforationspassing through the pre-existing blank material.

The methods, systems, and apparatuses are set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the methods, apparatuses,and systems. The advantages of the methods, apparatuses, and systemswill be realized and attained by means of the elements and combinationsparticularly pointed out in the appended claims. It is to be understoodthat both the foregoing general description and the following detaileddescription are exemplary and explanatory only and are not restrictiveof the methods, apparatuses, and systems, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying figures, like elements are identified by likereference numerals among the several preferred embodiments of thepresent invention.

FIG. 1 is a perspective view of the inventive graft.

FIG. 2A is a fragmentary plan view depicting a first pattern ofmicroperforations useful in the present invention.

FIG. 2B is a fragmentary plan view depicting a second pattern ofmicroperforations useful in the present invention.

FIG. 2C is a fragmentary plan view depicting a third pattern ofmicroperforations useful in the present invention.

FIG. 2D is a fragmentary plan view depicting a fourth pattern ofmicroperforations useful in the present invention.

FIG. 3A is photomicrograph depicting the inventive graft having thefirst pattern of microperforation depicted in FIG. 2A in a geometricallyundeformed state.

FIG. 3B is a photomicrograph of the inventive graft illustrated in FIG.3A showing the microperforations in a geometrically deformed state.

FIG. 4 is a diagrammatic illustration depicting geometric deformation ofthe fourth pattern of microperforations in FIG. 2D.

FIG. 5 is a diagrammatic cross-sectional view illustration depicting theinventive graft assuming a folded condition suitable for endoluminaldelivery.

FIG. 6 is a photographic illustration of the inventive graft as a stentcovering.

FIG. 7 is a photographic illustration of the inventive graft deformedapproximately 180 degrees along its longitudinal axis illustrating thefabric-like quality of the graft.

FIG. 8A is a photographic illustration of the inventive graftcircumferentially covering a braided expansion member and mounted on anexpansion jig that exerts a compressive force along the longitudinalaxis of the braided expansion member and which radially expands thebraided expansion member.

FIG. 8B is a photographic illustration of the inventive graft radiallyexhibiting radial compliance under the influence of a radially expansiveforce.

FIG. 9 is a flow diagram depicting alternate embodiments of making theinventive graft.

FIG. 10A is a histology slide, stained with hematoxylin and eosin, froma 28 day explanted swine carotid artery having the inventive graftimplanted therein.

FIG. 10B is a histology slide, stained with hematoxylin and eosin, froma 28 day explanted swine carotid artery having the inventive graftimplanted therein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

With the foregoing as background, we turn now to a description of thepresent invention with reference the preferred embodiments thereof andwith reference to the accompanying figures. As noted above, theinventive microporous metallic implantable devices may assume a widenumber of geometric configurations, including, for example, planarsheets, tubes or toroids. For ease of reference, however, theaccompanying figures and the following description of the invention willrefer to tubular implantable graft members. Those skilled in the art,however, will understand that this is merely an exemplary geometricconfiguration and is not intended to limit the scope of the invention totubular members or be limited in application to graft members.

The present invention relates generally to implantable metallic medicaldevices. More specifically, the present invention relates to implantablemedical devices, including, for example, surgical and endoluminalvascular grafts, stent grafts, skin grafts, shunts, bone grafts,surgical patches, non-vascular conduits, valvular leaflets, filters,occlusion membranes, sphincters, artificial tendons and ligaments. Morespecifically, the present invention relates to implantable medicalgrafts fabricated of metallic or pseudometallic films of biocompatiblematerials having a plurality of microperforations passing through thefilm. The plurality of microperforations may serve multiple purposes,including, for example, permitting geometric deformation of the film,imparting a fabric-like quality to the film, and imparting flexibilityto the film. The term “fabric-like” is intended to mean a quality ofbeing pliable and/or compliant in a manner similar to that found withnatural or synthetic woven fabrics.

The inventive implantable grafts are fabricated entirely ofself-supporting films made of biocompatible metals or biocompatiblepseudometals. Heretofore in the field of implantable medical devices, itis unknown to fabricate an implantable medical device that comprises agraft at least as one of its elements, such as a stent graft, entirelyof self-supporting metal or pseudometal materials. As used herein theterm “graft” is intended to indicate any type of device or part of adevice that comprises essentially a material delimited by two surfaceswhere the distance between said surfaces is the thickness of the graftand that exhibits integral dimensional strength and that hasmicroperforations that pass through the thickness of the graft. Theinventive grafts may be formed in planar sheets, toroids, and in othershapes as particular applications may warrant. However, for purposes ofillustration only, the present application will refer to tubular grafts.For purposes of this application, the terms “pseudometal” and“pseudometallic” are intended to mean a biocompatible material whichexhibits biological response and material characteristics substantiallythe same as biocompatible metals. Examples of pseudometallic materialsinclude, for example, composite materials and ceramics. Compositematerials are composed of a matrix material reinforced with any of avariety of fibers made from ceramics, metals, carbon, or polymers.

It is, therefore, desirable to fabricate the inventive graft of metallicand/or pseudometallic materials. The inventive metal devices may befabricated of pre-existing conventional wrought metallic materials, suchas stainless steel or nitinol hypotubes, or may be fabricated by thinfilm vacuum deposition techniques. In accordance with the presentinvention, it is preferable to fabricate the inventive implantabledevices by vacuum deposition. Vacuum deposition permits greater controlover many material characteristics and properties of the resultingformed device. For example, vacuum deposition permits control over grainsize, grain phase, grain material composition, bulk materialcomposition, surface topography, mechanical properties, such astransition temperatures in the case of a shape memory alloy. Moreover,vacuum deposition processes will permit creation of devices with greatermaterial purity without the introduction of large quantities ofcontaminants that adversely affect the material, mechanical orbiological properties of the implanted device. Vacuum depositiontechniques also lend themselves to fabrication of more complex devicesthan those susceptible of manufacture by conventional cold-workingtechniques. For example, multi-layer structures, complex geometricalconfigurations, extremely fine control over material tolerances, such asthickness or surface uniformity, are all advantages of vacuum depositionprocessing.

In vacuum deposition technologies, materials are formed directly in thedesired geometry, e.g., planar, tubular, etc. The common principle ofvacuum deposition processes is to take a material in a minimallyprocessed form, such as pellets or thick foils, known as the sourcematerial and atomize them. Atomization may be carried out using heat, asis the case in physical vapor deposition, or using the effect ofcollisional processes, as in the case of sputter deposition, forexample. In some forms of deposition, a process, such as laser ablation,which creates microparticles that typically consist of one or moreatoms, may replace atomization; the number of atoms per particle may bein the thousands or more. The atoms or particles of the source materialare then deposited on a substrate or mandrel to directly form thedesired object. In other deposition methodologies, chemical reactionsbetween ambient gases introduced into the vacuum chamber, i.e., the gassource, and the deposited atoms and/or particles are part of thedeposition process. The deposited material includes compound speciesthat are formed due to the reaction of the solid source and the gassource, such as in the case of chemical vapor deposition. In most cases,the deposited material is then either partially or completely removedfrom the substrate, to form the desired product.

A first advantage of vacuum deposition processing is that vacuumdeposition of the metallic and/or pseudometallic films permits tightprocess control and films may be deposited that have regular,homogeneous atomic and molecular pattern of distribution along theirfluid-contacting surfaces. This avoids the marked variations in surfacecomposition, creating predictable oxidation and organic adsorptionpatterns and has predictable interactions with water, electrolytes,proteins and cells. Particularly, EC migration is supported by ahomogeneous distribution of binding domains that serve as natural orimplanted cell attachment sites, in order to promote unimpeded migrationand attachment.

Secondly, in addition to materials and devices that are made of a singlemetal or metal alloy, henceforth termed a layer, the inventive graftsmay be comprised of a layer of biocompatible material or of a pluralityof layers of biocompatible materials formed upon one another into aself-supporting multilayer structure because multilayer structures aregenerally known to increase the mechanical strength of sheet materials,or to provide special qualities by including layers that have specialproperties such as superelasticity, shape memory, radio-opacity,corrosion resistance etc. A special advantage of vacuum depositiontechnologies is that it is possible to deposit layered materials andthus films possessing exceptional qualities may be produced (cf., H.Holleck, V. Schier: Multilayer PVD coatings for wear protection, Surfaceand Coatings Technology, Vol. 76-77 (1995) pp. 328-336). Layeredmaterials, such as superstructures or multilayers, are commonlydeposited to take advantage of some chemical, electronic, or opticalproperty of the material as a coating; a common example is anantireflective coating on an optical lens. Multilayers are also used inthe field of thin film fabrication to increase the mechanical propertiesof the thin film, specifically hardness and toughness.

Thirdly, the design possibilities for possible configurations andapplications of the inventive graft are greatly enhanced by employingvacuum deposition technologies. Specifically, vacuum deposition is anadditive technique that lends itself toward fabrication of substantiallyuniformly thin materials with potentially complex three dimensionalgeometries and structures that cannot be cost-effectively achieved, orin some cases achieved at all, by employing conventional wroughtfabrication techniques. Conventional wrought metal fabricationtechniques may entail smelting, hot working, cold working, heattreatment, high temperature annealing, precipitation annealing,grinding, ablation, wet etching, dry etching, cutting and welding. Allof these processing steps have disadvantages including contamination,material property degradation, ultimate achievable configurations,dimensions and tolerances, biocompatibility and cost. For exampleconventional wrought processes are not suitable for fabricating tubeshaving diameters greater than about 20 mm diameter, nor are suchprocesses suitable for fabricating materials having wall thicknessesdown to about 5 μm with sub-μm tolerances.

While the inventive self-supporting metal or pseudometal graft may befabricated of conventionally fabricated wrought materials, in accordancewith the best mode contemplated for the present invention, the inventivegraft is preferably fabricated by vacuum deposition techniques. Byvacuum depositing the metal and/or pseudometallic film as the precursormaterial for the inventive graft, it is possible to more stringentlycontrol the material, biocompatibility and mechanical properties of theresulting film material and graft than is possible with conventionallyfabricated graft-forming materials. The inventive self-supporting graftmay be used alone, i.e., the whole implantable device may be made of asingle graft, or it may be a part of a structure where the graft is usedin conjunction either with other grafts, or in conjunction with otherstructural elements, such as scaffolds, stents, and other devices. Theterm “in conjunction” may mean actual connection, such as that made bywelding, fusing, or other joining methods, as well as being made fromthe same piece of material by forming some area of the piece into agraft and some other area of the piece into another member or part ofthe device.

In accordance with a preferred embodiment of the invention, there isprovided a self-supporting graft member having a plurality ofmicroperforations passing through the wall thickness of the graft. Thegraft member may assume virtually any geometric configuration, includingsheets, tubes or rings. The plurality of microperforations may serve toimpart geometric compliance to the graft, geometric distendability tothe graft and/or limit or permit the passage of body fluids orbiological matter through the graft, such as facilitating transmuralendothelialization while preventing fluid flow through the wall of thegraft under normal physiological conditions. The plurality ofmicroperforations may also impart a fabric-like quality to the graft byimparting pliability and/or elastic, plastic or superelastic complianceto the graft, such as that required for longitudinal flexibility in thecase of a vascular graft.

In a first embodiment, the graft may be made from plastically deformablematerials such that upon application of a force, the microperforationsgeometrically deform to impart permanent enlargement of one or more axesof the graft, such as length in the case of a planar graft, e.g., asurgical patch graft, or diameter, such as in the case of a tubulargraft, e.g., a vascular graft. In a second embodiment, the graft may befabricated of elastic or superelastic materials. Elastic and/orsuperelastic materials will permit the microperforations togeometrically deform under an applied force in a manner that allows fora recoverable change in one or more axes of the graft.

In each of the first and second embodiments of the invention, the graftmay be fabricated in such a manner as to have fabric-like qualities bycontrolling the film thickness, material properties and geometry of theplurality of microperforations. Furthermore, in such cases whereminimally invasive delivery is required, such as for endoluminaldelivery of vascular grafts, the first and second embodiments allow fordelivery using balloon expansion and self-expansion, respectively, or acombination of both. Minimally invasive delivery may also beaccomplished by folding the graft for delivery similar to the manner inwhich an angioplasty balloon is creased and fluted or folded. The graftmay be delivered by unfolding the device in vivo either by assistancesuch as by using a balloon, or by the graft material's plastic, elasticor superelastic properties or by a combination thereof. After delivery,the plurality of microperforations may be patterned in such a manner asto allow for additional dimensional enlargement of the graft member byelastic or plastic deformation such as a radially expansive positivepressure.

For some applications it is preferable that the size of each of theplurality of microperforations be such as to permit cellular migrationthrough each opening, without permitting fluid flow there through. Inthis manner, for example, blood cannot flow through the plurality ofmicroperforations (in their deformed or un-deformed state), but variouscells or proteins may freely pass through the plurality ofmicroperforations to promote graft healing in vivo. For otherapplications, moderate amounts of fluid flow through the plurality ofdeformed or un-deformed microperforations may be acceptable. Forexample, endoluminal saphenous vein grafts may be fabricated withmicroperforations that serve the dual function of permitting transmuralendothelialization while also excluding biological debris, such asthrombus from passing through the wall thickness of the graft,effectively excluding detrimental matter from entering the circulation.In this example, each of the plurality of microperforations in eithertheir deformed or undeformed state, may exceed several hundred microns.

Those skilled in the art will understand that a direct relationshipexists between the size of pores and the overall ratio of expansion ordeformability of an implantable graft. Generally, therefore, it isappreciated that pore sizes must increase in order to increase theeffective attainable degree of expansion or deformation of the graft.

For applications where large deformation and small pore size are bothrequirements, in accordance with another aspect of the inventive graftembodiment, it is contemplated that two or more graft members areemployed such as diametrically concentric grafts for tubularconfigurations. The two or more graft members have a pattern of aplurality of microperforations passing there through, with the pluralityof patterned microperforations being positioned out of phase relative toone another such as to create a tortuous cellular migration pathwaythrough the wall of the concentrically engaged first and second graftmembers as well as a smaller effective pore size. In order to facilitatecellular migration through and healing of the first and second graftmembers in vivo, it may be preferable to provide additional cellularmigration pathways that communicate between the plurality ofmicroperforations in the first and second graft members. Theseadditional cellular migration pathways, if necessary, may be impartedas 1) a plurality of projections formed on either the luminal surface ofthe second graft or the abluminal surface of the first graft, or both,which serve as spacers and act to maintain an annular opening betweenthe first and second graft members that permits cellular migration andcellular communication between the plurality of microperforations in thefirst and second graft members, 2) a plurality of microgrooves, whichmay be random, radial, helical, or longitudinal relative to thelongitudinal axis of the first and second graft members, the pluralityof microgrooves being of a sufficient size to permit cellular migrationand propagation along the groove, the microgrooves serve as cellularmigration conduits between the plurality of microperforations in thefirst and second graft members, or 3) where the microperforations causeout of plane motion of the graft material upon deformation therebykeeping a well defined space between the planes originally defining thefacing surfaces of the grafts.

The graft member or members may be formed as a monolayer film, or may beformed from a plurality of film layers formed one upon another. Theparticular material used to form each layer of biocompatible metaland/or pseudometal is chosen for its biocompatibility, corrosion-fatigueresistance and mechanical properties, i.e., tensile strength, yieldstrength. The metals include, without limitation, the following:titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium,silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt,palladium, manganese, molybdenum and alloys thereof, such aszirconium-titanium-tantalum alloys, nitinol, and stainless steel.Additionally, each layer of material used to form the graft may be dopedwith another material for purposes of improving properties of thematerial, such as radiopacity or radioactivity, by doping with tantalum,gold, or radioactive isotopes.

With particular reference to FIG. 1, the inventive implantable medicaldevice is illustrated as a graft 10. Graft 10 consists generally of abody member 12 having a first surface 14 and a second surface 16 and athickness 18 intermediate the first surface 14 and the second surface16. A plurality of microperforations 20 is provided and passes throughthe thickness 18 of the body member 12 with interperforation regions 22of the body member 12 between adjacent microperforation 20. Theplurality of microperforations 20 each preferably has a geometricconfiguration that is susceptible of geometric change, such that theopen surface area of each microperforation 20 may change under anexternally applied load. Each of the plurality of microperforations 20in the undeformed state preferably has an open surface area less thanabout 2 mm², with the total open surface area of the graft in theundeformed state being between 0.001 to 99%. The open surface area ofthe plurality of microperforations and the open surface area of thegraft may change considerably upon deformation of the plurality ofmicroperforations 20. Both the size of the microperforations 20 in thedeformed and undeformed state and the total open area of the graft 12 inthe deformed and undeformed state may be selected in view of thefollowing non-exclusive factors based on the graft application: 1) thedesired compliance of the graft 10, 2) the desired strength of the graft10, 3) desired stiffness of the graft 10, 4) the desired degree ofgeometric enlargement of the microperforations 20 upon deformation and5) in some cases, such as with vascular grafts, the desired deliveryprofile and post delivery profile.

In accordance with a preferred embodiment of the present invention, theplurality of microperforations 20 is patterned in such a manner as todefine deformation regions of the body member 12. The thickness 18 isbetween 0.1 μm and 75 μm, preferably between 1 μm and 50 μm. Whenfabricated within these thickness ranges, the graft 10 has a thickness18 which is thinner than the wall thickness of conventional non-metallicimplantable grafts and that of conventional metal endoluminal stents.

The plurality of microperforations is patterned in a regular arrayforming a regular array of microperforations 20 in both the longitudinaland circumferential axes of the body member 12. For purposes ofreference, the pattern of microperforations 20 will, hereinafter, bedescribed with reference to a planar X-Y axes, which in a tubular memberwill correspond to the longitudinal or circumferential axes of thetubular member. Those of ordinary skill in the art will understand thatreference to X-axis or Y-axis when applied to a tubular member may beused such that the X-axis may correspond to either the longitudinal axisof circumferential direction of the tubular member and the Y-axis mayalso be translated to the corresponding circumferential direction orlongitudinal axis or the tubular member.

It will be appreciated by those of ordinary skill in the art thatindividual different geometric patterns may have associated intendeduses, function or mechanical requirements of a particular device. Thus,the particular intended use of the implantable member 12 will be aconsideration in the selection of the particular geometric pattern forthe plurality of microperforations 20. For example, where theimplantable member 12 has an intended use as a free-standing implantableendoluminal vascular graft, a large circumferential expansion ratio,significant hoop strength and longitudinal flexibility may be desirable.Thus, a particular geometry of the plurality of microperforations 20that offers these properties will be selected. The plurality ofmicroperforations 20 also affects the material properties of theimplantable member 10. For example, the geometry each microperforation20 may be altered so that each microperforation 20 exhibitsstress-strain relief capabilities or the microperforations 20 maycontrol whether geometric deformation of the microperforations 20 areplastic, elastic or superelastic deformation. Thus, both the geometry ofthe individual microperforations 20, the orientation of themicroperforations 20 relative to the X-Y axis of the implantable member10 and the pattern of the microperforations 20 may be selected todirectly impart, affect or control the mechanical and materialproperties of the implantable member 10.

Different geometric patterns for the plurality of microperforations 20in accordance with the preferred embodiments of the invention areillustrated in FIGS. 2A-2C. FIG. 2A illustrates a first geometry foreach of the plurality of microperforations 30. In accordance with thisfirst geometry, each of the plurality of microperforations 30 consist ofgenerally elongated slots 32 a, 32 b. Each of the generally elongatedslots 32 a, 32 b preferably include terminal fillets 34 on opposing endsof each elongated slot 32 a, 32 b. The terminal fillets 34 serve astrain relief function that aids in strain distribution through theinterperforation regions 22 between adjacent slots 32. FIG. 2A furtherillustrates a first geometric pattern for the plurality ofmicroperforations 32 a, 32 b, wherein a first row of a plurality ofmicroperforations 32 a is provided with adjacent microperforations 32 abeing arrayed in end-to-end fashion along a common axis, and a secondrow of a plurality of microperforations 32 b is provided with adjacentmicroperforations 32 b being arrayed in end-to-end fashion along acommon axis with one another and with the microperforations 32 a. Thefirst row of microperforations 32 a and the second row ofmicroperforations 32 b are offset or staggered from one another, with anend of a microperforation 32 a being laterally adjacent to anintermediate section of a microperforation 32 b, and an end ofmicroperforation 32 b being laterally adjacent an intermediate sectionof a microperforation 32 a.

The first geometry 30 of the plurality of microperforations 32 a, 32 billustrated in FIG. 2A permits a large deformation along an axisperpendicular to a longitudinal axis of the slots. Thus, where thelongitudinal axis of slots 32 a, 32 b is co-axial with the longitudinalaxis of the implantable member 10, deformation of the slots 32 a, 32 bwill permit circumferential compliance and/or expansion of theimplantable member 10. Alternatively, where the longitudinal axis of theslots 32 a, 32 b is parallel to the circumferential axis of theimplantable member 10, the slots 32 a, 32 b permit longitudinalcompliance, flexibility and expansion of the implantable member 10.

FIG. 2B illustrates a second geometry 40 for the plurality ofmicroperforations 20 and consists of a plurality of microperforations 42a, 44 b, again having a generally elongate slot-like configuration likethose of the first geometry 30. In accordance with this second geometry40, individual microperforations 42 a and 44 b are oriented orthogonalrelative to one another. Specifically, a first microperforation 42 a isoriented parallel to an X-axis of the implantable member 10, while afirst microperforation 44 b is positioned adjacent to the firstmicroperforation 44 a along the X-axis, but the first microperforation44 b is oriented perpendicular to the X-axis of the implantable member10 and parallel to the Y-axis of the implantable member 10. Like thefirst geometry, each of the plurality of microperforations 42 a, 44 bmay include a terminal fillet 44 at opposing ends of the slot of eachmicroperforation in order to serve a strain relief function and transmitstrain to the interperforation region 22 between adjacentmicroperforations. This second geometry 40 offers a balance in bothcompliance and degree of expansion in both the X and Y-axes of theimplantable device 12

In each of FIGS. 2A and 2B, each of the microperforations 32 a, 32 b, 42a, and 44 b has a generally longitudinal slot configuration. Each of thegenerally longitudinal slots may be configured as a generally linear orcurvilinear slot. In accordance with the preferred embodiments of theinvention, however, it is preferred to employ generally linear slots.

FIG. 2C illustrates a third preferred geometry 50 for the plurality ofmicroperforations. In accordance with this third geometry 50, each ofthe plurality of microperforations 52 has a generally trapezoidal ordiamond-like shape with interperforation graft regions 56 betweenadjacent pairs of microperforations 52. It will be appreciated that thethird geometry 50 may be achieved by geometrically deforming the firstgeometry 30 along an axis perpendicular to the longitudinal axis of theplurality of microperforations 32 a, 32 b. Similarly, the first geometry30 may be achieved by deforming microperforations 52 in the thirdgeometry 50 along either an X-axis or a Y-axis of the implantable member10.

FIGS. 3A and 3B are photomicrographs illustrating the inventiveimplantable device 12 having a plurality of microperforations formed asgenerally longitudinal slots 32 a, 32 b in accordance with the firstgeometry depicted in FIG. 2A. Each of the plurality of microperforationswas formed with an orientation parallel to the longitudinal axis of theimplantable device 12. The implantable device 12 consists of a 6 mminner diameter NiTi shape memory tubular graft member having a wallthickness of 5 μm. FIG. 3A depicts the plurality of microperforations 32a and 32 b in their undeformed state, while FIG. 3B depicts theplurality of microperforations 32 a and 32 b in their geometricallydeformed state under the influence of an strain applied perpendicular tothe longitudinal axis of the implantable graft 12. It may be clearlyunderstood that geometric deformation of the plurality ofmicroperforations 32 a, 32 b permitted circumferential expansion of theinventive graft. The dimensions of each of the plurality ofmicroperforations in their undeformed state depicted in FIGS. 3A and 3Bwas 430 μm in length, 50 μm width, with the terminal fillets having a 50μm diameter.

In accordance with a fourth geometry of the plurality ofmicroperforations 20 illustrated in FIGS. 2D and 4, each of theplurality of microperforations 20 have a generally tri-legged orY-shaped configuration. The Y-shaped configuration of each of theplurality of microperforations 20 has three co-planar radiallyprojecting legs 31 a, 31 b, 31 c, each offset from the other by an angleof about 120 degrees thereby forming a generally Y-shape. Each of thethree co-planar radially projecting legs 31 a, 31 b, and 31 c may besymmetrical or asymmetrical relative to one another. However, in orderto achieve uniform geometric deformation across the entire graft bodymember 12, it is preferable that each of the plurality ofmicroperforations 20 has geometric symmetry. Those skilled in the artwill recognize that beyond the two particular patterns described hereany number of different patterns may be used without significantlydeparting from the inventive graft concept described in the presentpatent.

Those skilled in the art will understand that each of themicroperforations 20 are capable of undergoing deformation uponapplication of a sufficient force. In a tubular geometry, the graft 12may deform both circumferentially and longitudinally. As is illustratedin FIG. 3b , each of the plurality of elongated slots may deform intoopened microperforations which assume a generally rhomboidal shape.Similarly, Y-shaped microperforations 20 shown in FIG. 4 are capable ofdeformation into generally circular or oval open microperforations 21.The deformation regions 22 between adjacent microperforations 20facilitate deformation of each of the plurality of microperforations 20by deforming to accommodate opening of each of the plurality ofmicroperforations 20.

As depicted in FIG. 5, the inventive graft 12 may be folded to assume asmaller diametric profile for endoluminal delivery. In order tofacilitate folding, the pattern of the plurality of microperforations 20may be fashioned to create a plurality of folding regions 23, thatconstitute relatively weakened regions of the graft 12, to permitfolding the graft 12 along folding regions 23.

FIG. 6 is a photographic illustration of the inventive microporous graft12 circumferentially mounted onto an endoluminal stent 5. It may bereadily seen that the microporous graft 12 exhibits mechanicalproperties of high longitudinal flexibility and both radial andcircumferential compliance.

FIG. 7 is a photographic illustration of the inventive microporous graft12 mounted onto mandrel and flexed approximately 180 degrees along itslongitudinal axis. Upon longitudinal flexion, the inventive graft 12undergoes a high degree of folding with a plurality of circumferentiallyoriented folds 7, characteristic of its fabric-like qualities.

FIGS. 8A and 8B are photographic reproductions illustrating the highdegree of circumferential compliance of the inventive microporous graft12. A 6 mm microporous graft having a 5 μm wall thickness was mountedconcentrically over a braided pseudostent. An axial force was appliedalong the longitudinal axis of the braided pseudostent causing thepseudostent to radially expand and exert a circumferentially expansiveforce to the inventive graft 12. As is clearly depicted in FIGS. 8A and8B, the plurality of micropores in the inventive graft 12 geometricallydeform thereby permitting circumferential expansion of the graft 12.

Thus, one embodiment of the present invention provides a new metallicand/or pseudometallic implantable graft that is biocompatible,geometrically changeable either by folding and unfolding or byapplication of a plastically, elastically or superelastically deformingforce, and capable of endoluminal delivery with a suitably smalldelivery profile. Suitable metal materials to fabricate the inventivegraft are chosen for their biocompatibility, mechanical properties,i.e., tensile strength, yield strength, and their ease of fabrication.The compliant nature of the inventive graft material may be employed toform the graft into complex shapes by deforming the inventive graft overa mandrel or fixture of the appropriate design. Plastic deformation andshape setting heat treatments may be employed to ensure the inventiveimplantable members 10 retain a desired conformation.

According to a first preferred method of making the graft of the presentinvention, the graft is fabricated of vacuum deposited metallic and/orpseudometallic films. With particular reference to FIG. 9, thefabrication method 100 of the present invention is illustrated. Aprecursor blank of a conventionally fabricated biocompatible metal orpseudometallic material may be employed at step 102. Alternatively, aprecursor blank of a vacuum deposited metal or pseudometallic film maybe employed at step 104. The precursor blank material obtained eitherfrom step 102 or step 104 is then preferably masked at step 108 leavingexposed only those regions defining the plurality of microperforations.The exposed regions from step 108 are then subjected to removal eitherby etching at step 110, such as by wet or dry chemical etchingprocessing, with the etchant being selected based upon the material ofthe precursor blank, or by machining at step 112, such as by laserablation or EDM. Alternatively, when employing the vacuum depositionstep 104, a pattern mask corresponding to the plurality ofmicroperforations may be interposed at step 106 between the target andthe source and the metal or pseudometal deposited through the patternmask to form the patterned microperforations. Further, when employingthe vacuum deposition step 104, plural film layers maybe deposited toform a multilayer film structure of the film prior to or concurrentlywith forming the plurality of microperforations.

Thus, the present invention provides a new metallic and/orpseudometallic implantable graft that is biocompatible, compliant, andgeometrically changeable either by folding and unfolding or byapplication of a plastically, elastically or superelastically deformingforce, and, in some cases, capable of endoluminal delivery with asuitably small delivery profile and suitably low post-delivery profile.Suitable metal materials to fabricate the inventive graft are chosen fortheir biocompatibility, mechanical properties, i.e., tensile strength,yield strength, and in the case where vapor deposition is deployed,their ease of deposition include, without limitation, the following:titanium, vanadium, aluminum, nickel, tantalum, zirconium, chromium,silver, gold, silicon, magnesium, niobium, scandium, platinum, cobalt,palladium, manganese, molybdenum and alloys thereof, such aszirconium-titanium-tantalum alloys, nitinol, and stainless steel.Examples of pseudometallic materials potentially useful with the presentinvention include, for example, composite materials and ceramics.

The present invention also provides a method of making the inventiveexpandable metallic graft by vacuum deposition of a graft-forming metalor pseudometal and formation of the microperforations either by removingsections of deposited material, such as by etching, EDM, ablation, orother similar methods, or by interposing a pattern mask, correspondingto the microperforations, between the target and the source duringdeposition processing. Alternatively, a pre-existing metal and/orpseudometallic film manufactured by conventional non-vacuum depositionmethodologies, such as wrought hypotube or sheet, may be obtained, andthe microperforations formed in the pre-existing metal and/orpseudometallic film by removing sections of the film, such as byetching, EDM, ablation, or other similar methods. An advantage ofemploying multilayer film structures to form the inventive graft is thatdifferential functionalities may be imparted in the discrete layers. Forexample, a radiopaque material such as tantalum may form one layer of astructure while other layers are chosen to provide the graft with itsdesired mechanical and structural properties.

In accordance with the preferred embodiment of fabricating the inventivemicroporous metallic implantable device in which the device isfabricated from vacuum deposited nitinol tube, a cylindricaldeoxygenated copper substrate is provided. The substrate is mechanicallyand/or electropolished to provide a substantially uniform surfacetopography for accommodating metal deposition thereupon. A cylindricalhollow cathode magnetron sputtering deposition device was employed, inwhich the cathode was on the outside and the substrate was positionedalong the longitudinal axis of the cathode. A cylindrical targetconsisting either of a nickel-titanium alloy having an atomic ratio ofnickel to titanium of about 50-50% and which can be adjusted by spotwelding nickel or titanium wires to the target, or a nickel cylinderhaving a plurality of titanium strips spot welded to the inner surfaceof the nickel cylinder, or a titanium cylinder having a plurality ofnickel strips spot welded to the inner surface of the titanium cylinderis provided. It is known in the sputter deposition arts to cool a targetwithin the deposition chamber by maintaining a thermal contact betweenthe target and a cooling jacket within the cathode. In accordance withthe present invention, it has been found useful to reduce the thermalcooling by thermally insulating the target from the cooling jacketwithin the cathode while still providing electrical contact to it. Byinsulating the target from the cooling jacket, the target is allowed tobecome hot within the reaction chamber. Two methods of thermallyisolating the cylindrical target from the cooling jacket of the cathodewere employed. First, a plurality of wires having a diameter of 0.0381mm were spot welded around the outer circumference of the target toprovide an equivalent spacing between the target and the cathode coolingjacket. Second, a tubular ceramic insulating sleeve was interposedbetween the outer circumference of the target and the cathode coolingjacket. Further, because the Ni—Ti sputtering yields can be dependant ontarget temperature, methods which allow the target to become uniformlyhot are preferred.

The deposition chamber was evacuated to a pressure less than or about2-5×10⁻⁷ Torr and pre-cleaning of the substrate is conducted undervacuum. During the deposition, substrate temperature is preferablymaintained within the range of 300 and 700 degrees Centigrade. It ispreferable to apply a negative bias voltage between 0 and −1000 volts tothe substrate, and preferably between −50 and −150 volts, which issufficient to cause energetic species arriving at the surface of thesubstrate. During deposition, the gas pressure is maintained between 0.1and 40 mTorr but preferably between 1 and 20 mTorr. Sputteringpreferably occurs in the presence of an Argon atmosphere. The argon gasmust be of high purity and special pumps may be employed to reduceoxygen partial pressure. Deposition times will vary depending upon thedesired thickness of the deposited tubular film. After deposition, theplurality of microperforations are formed in the tube by removingregions of the deposited film by etching, such as chemical etching,ablation, such as by excimer laser or by electric discharge machining(EDM), or the like. After the plurality of microperforations are formed,the formed microporous film is removed from the copper substrate byexposing the substrate and film to a nitric acid bath for a period oftime sufficient to remove dissolve the copper substrate.

EXAMPLE

A 5 μm thick NiTi graft having a pattern of microperforations consistingof parallel staggered longitudinally oriented linear slots, each slotbeing 430 μm length, 25 μm width, and having 50 μm diameter fillets oneach end of each linear slot, was mounted onto a 6 mm NiTi stent anddelivered endoluminally to the left carotid artery of a swine. After 28days, the swine was euthanized, and the graft explanted from the leftcarotid artery. Samples were prepared using standard hematoxylin andeosin staining procedures, and microscope slides prepared. Asillustrated in FIG. 10A, histology of the explanted samples revealedcomplete endothelialization around the graft 12, negligible neointimalproliferation with the absence of trauma to the internal elastic lamina.FIG. 10B is a sample indicating cross-talk between the arterialsuperficial and deep layers with the transmural formation of smallcapillaries.

While the present invention has been described with reference to itspreferred embodiments, those of ordinary skill in the art willunderstand and appreciate that variations in materials, dimensions,geometries, and fabrication methods may be or become known in the art,yet still remain within the scope of the present invention which islimited only by the claims appended hereto.

What is claimed is:
 1. An implantable medical device, comprising: a. anon-coiled tubular body member consisting essentially of a metallic orpseudometallic material film having a first surface, a second surfaceand a thickness intermediate the first surface and the second surface,the thickness being between 0.1 μm to 75 μm; and b. a plurality ofmicroperforations passing through the thickness of the body member andcommunicating between the first surface and the second surface, wherebysaid plurality of microperforations are configured to geometricallydeform, thereby allowing diametric expansion and both circumferentialand longitudinal compliance of the body member.
 2. The implantablemedical device according to claim 1, wherein the body member furthercomprises a generally torroidal annular ring-shaped member.
 3. Theimplantable medical device according to claim 1, wherein the thicknessof the body member between 0.1 μm and 50 μm.
 4. The implantable medicaldevice according to claim 1, wherein the plurality of microperforationsare arrayed in at least one pattern sufficient to impart at least one ofcompliance and pliability to the body member.
 5. The implantable medicaldevice according to claim 4, wherein said plurality of microperforationsfurther comprise a plurality of slots arrayed substantially parallel toat least one of a longitudinal axis and a circumferential direction ofthe body member.
 6. The implantable medical device according to claim 5,wherein each of the plurality of slots has a generally elongate linearconfiguration.
 7. The implantable medical device according to claim 6,wherein each of the plurality of slots further comprise terminal filletspositioned at opposing ends of each of the plurality of slots, whereinthe terminal fillets include a diameter larger than a width of theplurality of slots.
 8. The implantable medical device according to claim7, wherein the elongated slot configuration further comprises a firstplurality of slots oriented parallel to the longitudinal axis of thebody member and a second plurality of slots oriented parallel to thecircumferential axis of the body member, the first plurality of slotsand the second plurality of slots being positioned generally orthogonalrelative to one another.
 9. The implantable medical device according toclaim 1, wherein said plurality of microperforations further comprise aplurality of generally diamond-shaped openings.
 10. The implantablemedical device according to claim 1, wherein each of the plurality ofmicroperforations have an open surface area less than about 2 mm² whenthe body member is in an undeformed state.
 11. The implantable medicaldevice according to claim 1, wherein the plurality of microperforationscreate a total open surface area of the body member in an undeformedstate between about 0.001 to 99%.
 12. The implantable medical deviceaccording to claim 1, wherein the body member thickness is within therange of about 0.1 μm to 75 μm.
 13. The implantable medical deviceaccording to claim 12, wherein the body member thickness is within therange of about 1 μm to 50 μm.
 14. A method of fabricating the bodymember according to claim 1, comprising the steps of: a. Providing asacrificial substrate suitable; b. Vacuum depositing at least one of ametallic and pseudometallic biocompatible material onto the sacrificialsubstrate thereby forming a film of the biocompatible material; c.Imparting a plurality of microperforations passing through the film ofbiocompatible material thereby forming the implantable medical device;and d. Separating the sacrificial substrate from the formed implantablemedical device.
 15. The method according to claim 14, wherein the stepc. further comprises the step of removing portions of the biocompatiblematerial to form the plurality of microperforations.
 16. The methodaccording to claim 14, wherein the removing step is selected from thesteps of chemical etching, laser ablation and electrical dischargemachining.
 17. A method of fabricating the body member according toclaim 1, comprising the steps of: a. providing a pre-existing blank ofat least one of a biocompatible metallic and pseudometallic material; b.removing sections of the pre-existing blank material to form a pluralityof microperforations passing through the pre-existing blank material.